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Review

Annals of Internal Medicine

Antipsychotics in Adults With Schizophrenia: Comparative Effectiveness of First-Generation Versus Second-Generation Medications

A Systematic Review and Meta-analysis

Lisa Hartling, PhD; Ahmed M. Abou-Setta, MD, PhD; Serdar Dursun, MD, PhD; Shima S. Mousavi, MD; Dion Pasichnyk, BSc; and Amanda S. Newton, RN, PhD

Background: Debate continues about the comparative benefits and harms of first-generation antipsychotics (FGAs) and second- generation antipsychotics (SGAs) in treating schizophrenia.

Purpose: To compare the effects of FGAs with those of SGAs in the treatment of adults aged 18 to 64 years with schizophrenia and related psychosis on illness symptoms, diabetes mellitus, mortality, tardive dyskinesia, and a major metabolic syndrome.

Data Sources: English-language studies from 10 electronic data- bases to March 2012, reference lists of relevant articles, and gray literature.

Study Selection: Randomized trials for efficacy and cohort studies at least 2 years in duration for adverse events.

Data Extraction: Two independent reviewers extracted data from 114 studies involving 22 comparisons and graded the strength of evidence for primary outcomes as insufficient, low, moderate, or high using the Grading of Recommendations Assessment, Devel- opment and Evaluation approach.

Data Synthesis: Few differences of clinical importance were found for core illness symptoms; lack of precision in effect estimates precluded firm conclusions for many comparisons. Moderate- strength evidence showed a clinically important benefit of haloper- idol over olanzapine for improving positive symptoms, but the benefit was scale-dependent: It was seen when the Scale for the Assessment of Positive Symptoms was used but not when the Pos- itive and Negative Syndrome Scale (PANSS) was used. Moderate-

strength evidence showed a clinically important benefit of olanzap- ine over haloperidol in improving negative symptoms when the PANSS and the Scale for the Assessment of Negative Symptoms were used. Low-strength evidence showed no difference in mor- tality for chlorpromazine verus clozapine or haloperidol versus arip- iprazole, increased incidence of the metabolic syndrome for olan- zapine versus haloperidol (risk differences, 2% and 22%), and higher incidence of tardive dyskinesia for chlorpromazine versus clozapine (risk differences, 5% and 9%). Evidence was insufficient to draw conclusions for diabetes mellitus.

Limitations: All studies had high or unclear risk of bias. Length of study follow-up was often too brief to adequately measure adverse events. Medication comparisons, dosage, and outcome measure- ment were heterogenous for head-to-head comparisons. Selective patient populations limit generalizability.

Conclusion: Clear benefits of FGAs versus SGAs for treating schizo- phrenia remain inconclusive because of variation in assessing out- comes and lack of clinically important differences for most compar- isons. The strength of evidence on safety for major medical events is low or insufficient.

Primary Funding Source: Agency for Healthcare Research and Quality.

Ann Intern Med. 2012;157:498-511. For author affiliations, see end of text. This article was published at www.annals.org on 14 August 2012.

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T he introduction of second-generation antipsychotics (SGAs) for treatment of schizophrenia was an impor-

tant effort to improve symptom management, reduce ex- trapyramidal symptoms caused by first-generation antipsy- chotics (FGAs), and offer patients improved quality of life and functioning. Today, 20 commercial FGAs and SGAs that have been approved by the U.S. Food and Drug Ad- ministration (FDA) are available in the United States (Ap- pendix Table 1, available at www.annals.org). Of these, SGAs are more frequently prescribed by physicians. In 2003, three quarters of the 2 million adult patients in the United States who were prescribed an antipsychotic medi- cation were prescribed an SGA, which accounted for 93% of the estimated $2.82 billion spent on these medications in the United States (1). Recent large-scale trials and meta-analyses have called into question whether SGAs and FGAs provide clinically important differences for patient outcomes (1–3), and the question of which medication is more efficacious has yet to

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be definitively answered. Part of the uncertainty about medication efficacy relates to the lack of studies focused on long-term management. Such issues as how patient man- agement should be influenced by medication heterogeneity within the 2 classes also add ambiguity for physician deci- sion making (1, 4 – 6), as do differences between recently published reviews in defining eligible medication compar- isons, patients, and clinically important outcomes and eval- uating the strength of evidence (1, 7–19). This comparative effectiveness review summarizes the benefits and harms associated with commercially available, FDA-approved FGAs and SGAs. Broad inclusion criteria were used for comparisons among FGAs and SGAs, pa- tients, and study outcomes to address the diversity of pre- viously published reviews.

METHODS

We followed an open process for this review with in- put from various stakeholders, including the public (20),

First- vs. Second-Generation Antipsychotics in Adults With Schizophrenia

Review

and a protocol that followed standards for systematic re- views (21–23). A full technical report with detailed search strategies, methods, and evidence tables is available from the Agency for Healthcare Research and Quality (21).

Literature Search

We conducted comprehensive searches in MEDLINE (Appendix Table 2, available at www.annals.org), EMBASE, PsycINFO, International Pharmaceutical Abstracts, CINAHL, ProQuest Dissertations and Theses—Full Text, the Co- chrane Central Register of Controlled Trials, and Scopus for studies published from 1950 to March 2012. For ad- verse events, we also searched the U.S. National Library of Medicine’s TOXLINE and the MedEffect Canada Adverse Reaction Database. We hand-searched proceedings from the annual meet- ings of the American Psychiatric Association (2008 –2010) and the International College of Neuropsychopharmacol- ogy (2008 –2010). We searched clinical trial registries and contacted experts in the field and authors of relevant stud- ies. We retrieved new drug applications for each of the included interventions from the FDA Web site. We re- viewed the reference lists of reviews, guidelines, and new drug applications and searched for articles citing relevant studies using Scopus Citation Tracker.

Study Selection

Two reviewers independently screened titles and ab- stracts. We retrieved the full text of potentially relevant studies. Two reviewers independently reviewed each article

using a standardized form with a priori eligibility criteria

( Appendix Table 3, available at www.annals.org). We re-

solved discrepancies through discussion or third-party ad- judication. We included studies if they were randomized, controlled trials (RCTs); were nonrandomized, controlled trials (non-RCTs); were cohort studies with a minimum follow-up of 2 years; included adults aged 18 to 64 years with schizophrenia or related psychoses; compared a com- mercially available FDA-approved FGA with an FDA- approved SGA; and provided data on illness symptoms

( Appendix Table 4, available at www.annals.org) or the

following adverse events: diabetes mellitus, death, tardive dyskinesia, or a major metabolic syndrome.

Quality Assessment and Rating the Body of Evidence

Two reviewers independently assessed the method- ological quality of included studies and resolved disagree- ments through discussion. We assessed RCTs and non- RCTs using the Cochrane Risk of Bias Tool (22) and cohort studies using the Newcastle–Ottawa Scale (24). Two reviewers independently evaluated strength of ev- idence using the Grading of Recommendations Assess- ment, Development and Evaluation approach of the Evidence-based Practice Center Program and resolved dis- crepancies through discussion (25). We examined 4 do- mains: risk of bias, consistency, directness, and precision. Within the grading system, randomized trials always begin with a “high” strength of evidence that can be downgraded

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on the basis of shortcomings in the body of evidence (for example, overall risk of bias, inconsistency between study results, indirectness of the measured outcomes, and impre- cision of the pooled estimate). In contrast, observational studies (for example, cohort studies) begin with a “low” strength of evidence that can be further downgraded (sim- ilar to randomized trials) but can also, in rare cases, be upgraded. We assigned an overall grade of “high,” “mod- erate,” “low,” or “insufficient” strength of evidence. We graded core illness symptoms in the categories of positive symptoms, negative symptoms, general psychopathology, and global ratings or total scores (typically a compilation of positive and negative symptoms or general psychopathol- ogy, which included these symptoms plus mood states). We provided a grade for each scale that was reported in the relevant studies. We also graded the adverse events listed in the previous section.

Data Extraction

Two reviewers independently extracted data using standardized forms and resolved discrepancies by referring to the original report. We extracted information on study characteristics, populations, interventions, outcomes, and results. Primary outcomes were improved core symptoms

Figure. Summary of evidence search and selection.

Records identified

through database searches

( n = 11 775)

Additional records identified through other sources

( n = 286)

records identified through other sources ( n = 286) Records remaining after duplicates removed ( n
Records remaining after duplicates removed ( n = 9703)

Records remaining after duplicates removed (n = 9703)

Records remaining after duplicates removed ( n = 9703)
Records remaining after duplicates removed ( n = 9703)

Records screened (n = 9703)

removed ( n = 9703) Records screened ( n = 9703) Records excluded ( n =

Records excluded (n = 8487)

Full-text articles assessed for eligibility

( n = 1216)

Full-text articles assessed for eligibility ( n = 1216) Full-text articles excluded ( n = 953)
Full-text articles assessed for eligibility ( n = 1216) Full-text articles excluded ( n = 953)

Full-text articles excluded (n = 953) Publication type or study design: 622 Non–English-language: 100 Population or intervention: 151 No extractable data available: 63 Unavailable publication: 17

Studies included in quantitative or qualitative synthesis (n = 263) Primary publications: 114 Companion publications: 149

= 263) Primary publications: 114 Companion publications: 149 499 2 October 2012 Annals of Internal Medicine
= 263) Primary publications: 114 Companion publications: 149 499 2 October 2012 Annals of Internal Medicine
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Annals of Internal Medicine

Volume 157 • Number 7

Table 1. Summary of Results and Strength of Evidence for Core Illness Symptoms*

Review

First- vs. Second-Generation Antipsychotics in Adults With Schizophrenia

Variable, Scale, and Comparison

Studies

Risk of

Consistency

Precision

Mean Difference

Favored

Strength of

(Participants),

Bias

(95% CI)

Drug

Evidence

n (n)

Positive symptoms

PANSS

Haloperidol vs. risperidone

22 (4142)

Medium

Consistent

Precise

0.77 (0.09 to 1.45)†

Risperidone‡

Low§

Haloperidol vs. clozapine

3 (184)

Medium

Consistent

Imprecise

0.82 ( 2.21 to 0.57)

Low

Haloperidol vs. olanzapine

14 (3742)

Medium

Consistent

Imprecise

0.43 ( 0.22 to 1.08)

Low

Haloperidol vs. quetiapine

3 (358)

Medium

Consistent

Imprecise

0.83 ( 0.29 to 1.95)

Low

Haloperidol vs. aripiprazole

2 (407)

Medium

Consistent

Imprecise

0.99 ( 2.64 to 0.67)

Low

SAPS Haloperidol vs. olanzapine

2 (178)

Medium

Consistent

Precise

3.14 ( 4.90 to 1.37)†

Haloperidol

Moderate

Haloperidol vs. risperidone

2 (195)

Medium

Consistent

Imprecise

0.26 ( 1.90 to 1.38)

Low

Negative symptoms PANSS Haloperidol vs. olanzapine

14 (3742)

Medium

Consistent

Precise

1.06 (0.46 to 1.67)†

Olanzapine

Moderate

Haloperidol vs. aripiprazole

3 (1701)

Medium

Consistent

Precise

0.80 (0.14 to 1.46)†

Aripiprazole‡

Moderate

Haloperidol vs. risperidone

22 (4142)

Medium

Consistent

Precise

0.61 (0.07 to 1.16)†

Risperidone‡

Moderate

Haloperidol vs. clozapine

3 (184)

Medium

Consistent

Imprecise

0.28 ( 0.96 to 1.51)

Low

Haloperidol vs. quetiapine

3 (358)

Medium

Consistent

Imprecise

0.53 ( 0.81 to 1.87)

Low

Haloperidol vs. ziprasidone

2 (900)

Medium

Consistent

Imprecise

0.56 ( 0.30 to 1.42)

Low

SANS Haloperidol vs. olanzapine

5 (535)

Medium

Consistent

Precise

2.56 (0.94 to 4.18)†

Olanzapine

Moderate

Haloperidol vs. risperidone

4 (508)

Medium

Consistent

Imprecise

0.30 ( 2.79 to 3.38)

Low

Haloperidol vs. clozapine

2 (157)

Medium

Consistent

Imprecise

0.94 ( 2.60 to 4.48)

Low

Global ratings and total scores PANSS

Haloperidol vs. risperidone

21 (4020)

Medium

Consistent

Precise

3.24 (1.62 to 4.86)

Risperidone

Moderate

Haloperidol vs. olanzapine

15 (4209)

Medium

Consistent

Precise

2.31 (0.44 to 4.18)†

Olanzapine

Moderate

Haloperidol vs. clozapine

4 (607)

Medium

Consistent

Imprecise

2.69 ( 1.28 to 6.65)

Low

Haloperidol vs. quetiapine

5 (1013)

Medium

Consistent

Imprecise

0.31 ( 2.34 to 2.96)

Low

Haloperidol vs. ziprasidone

4 (1105)

Medium

Consistent

Imprecise

1.22 ( 0.62 to 3.07)

Low

BPRS Chlorpromazine vs. clozapine

6 (535)

Medium

Consistent

Precise

8.40 (5.92 to 10.88)†

Clozapine

Moderate

Haloperidol vs. aripiprazole

3 (779)

Medium

Consistent

Imprecise

0.01 ( 2.82 to 2.81)

Low

Haloperidol vs. risperidone

14 (2659)

Medium

Consistent

Imprecise

0.67 ( 0.53 to 1.88)

Low

Haloperidol vs. quetiapine

4 (756)

Medium

Consistent

Imprecise

1.23 ( 0.50 to 2.96)

Low

Haloperidol vs. clozapine

4 (268)

Medium

Consistent

Imprecise

2.16 ( 0.56 to 4.87)

Low

Haloperidol vs. olanzapine

13 (4014)

Medium

Consistent

Imprecise

0.19 ( 2.09 to 2.47)

Low

Haloperidol vs. ziprasidone CGI-S

4 (1078)

Medium

Consistent

Imprecise

0.24 ( 0.57 to 1.06)

Low

Haloperidol vs. olanzapine

8 (3564)

Medium

Consistent

Precise

0.16 (0.01 to 0.31)†

Olanzapine‡

Moderate

Haloperidol vs. quetiapine

4 (1253)

Medium

Consistent

Precise

0.23 ( 0.42 to 0.04)†

Haloperidol‡

Moderate

Haloperidol vs. aripiprazole

5 (1366)

Medium

Consistent

Imprecise

0.03 ( 0.20 to 0.14)

Low

Haloperidol vs. risperidone

8 (2348)

Medium

Consistent

Imprecise

0.07 ( 0.11 to 0.25)

Low

Haloperidol vs. ziprasidone

4 (1143)

Medium

Consistent

Imprecise

0.00 ( 0.26 to 0.26)

Low

CGI-I Haloperidol vs. olanzapine

2 (281)

Medium

Consistent

Imprecise

0.11 ( 0.30 to 0.51)

Low

Haloperidol vs. quetiapine

3 (623)

Medium

Consistent

Imprecise

0.02 ( 0.24 to 0.27)

Low

Haloperidol vs. risperidone GAF

3 (657)

Medium

Consistent

Imprecise

0.02 ( 0.39 to 0.36)

Low

Haloperidol vs. ziprasidone

3 (1085)

Medium

Consistent

Imprecise

0.30 ( 1.58 to 2.19)

Low

General psychopathology PANSS Haloperidol vs. clozapine

3 (184)

Medium

Consistent

Imprecise

1.77 ( 2.99 to 6.53)

Low

Haloperidol vs. olanzapine

10 (1187)

Medium

Consistent

Imprecise

0.53 ( 1.20 to 2.25)

Low

Haloperidol vs. quetiapine

3 (358)

Medium

Consistent

Imprecise

1.55 ( 0.29 to 3.38)

Low

Haloperidol vs. risperidone

16 (3036)

Medium

Consistent

Imprecise

0.87 ( 0.48 to 2.21)

Low

HAM-D Haloperidol vs. olanzapine

3 (209)

Medium

Consistent

Imprecise

1.14 ( 0.60 to 2.89)

Low

Haloperidol vs. risperidone

2 (408)

Medium

Consistent

Imprecise

0.64 ( 1.97 to 0.69)

Low

HAM-A Haloperidol vs. olanzapine MADRS

2 (283)

Medium

Consistent

Imprecise

0.90 ( 0.43 to 2.23)

Low

Haloperidol vs. olanzapine

6 (2639)

Medium

Consistent

Precise

2.46 (1.78 to 3.14)†

Olanzapine

Moderate

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Table 1—Continued

First- vs. Second-Generation Antipsychotics in Adults With Schizophrenia

Review

Variable, Scale, and Comparison

Studies

Risk of

Consistency

Precision

Mean Difference

Favored

Strength of

(Participants),

Bias

(95% CI)

Drug

Evidence

n (n)

CDSS Haloperidol vs. olanzapine

3 (344)

Medium

Consistent

Imprecise

0.61 ( 0.47 to 1.68)

Low

Haloperidol vs. quetiapine

2 (232)

Medium

Consistent

Imprecise

0.03 ( 0.52 to 0.58)

Low

Haloperidol vs. risperidone ABS

3 (485)

Medium

Consistent

Imprecise

0.24 ( 0.94 to 0.46)

Low

Haloperidol vs. olanzapine

2 (482)

Medium

Consistent

Imprecise

0.80 ( 1.22 to 2.83)

Low

ACES Haloperidol vs. olanzapine YMRS

2 (482)

Medium

Consistent

Imprecise

0.06 ( 0.40 to 0.53)

Low

Haloperidol vs. risperidone

2 (408)

Medium

Consistent

Imprecise

0.02 ( 0.67 to 0.71)

Low

ABS Agitated Behavior Scale; ACES Agitation–Calmness Evaluation Scale; BPRS Brief Psychiatric Rating Scale; CDSS Calgary Depression Scale for Schizo- phrenia; CGI-I Clinical Global Impression—Improvement; CGI-S Clinical Global Impression—Severity; GAF Global Assessment of Functioning; HAM-A Hamilton Rating Scale for Anxiety; HAM-D Hamilton Rating Scale for Depression; MADRS Montgomery–Asberg Depression Rating Scale; PANSS Positive and Negative Syndrome Scale; SANS Scale for the Assessment of Negative Symptoms; SAPS Scale for the Assessment of Positive Symptoms; YMRS Young Mania Rating Scale. * All trials provided results from direct comparisons. Statistically significant result. Result was not clinically important (difference 20%). § Downgraded from moderate to low for publication bias. Statistically significant result with outlier removed.

of illness (positive and negative symptoms and general psy- chopathology) and 4 adverse events specified a priori. Sec- ondary outcomes included functional outcomes; health care system use; response, remission, and relapse rates and medication adherence; health-related quality of life; other patient-oriented outcomes (for example, patient satisfac- tion); and general and specific measures of other adverse events (for example, extrapyramidal symptoms and weight gain). When studies incorporated multiple relevant treat- ment groups or multiple follow-up periods, we extracted data from all groups for the longest follow-up period. In cases of multiple reports of the same study, we referenced the primary, or most relevant, study and extracted addi- tional data from companion reports.

Data Analysis

We conducted meta-analyses in RevMan, version 5.01 (The Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark), using a random-effects model (26) when studies were sufficiently similar in terms of de- sign, population, interventions, and outcomes. We com- bined risk ratios for dichotomous outcomes using the Der- Simonian and Laird random-effects model and combined continuous outcomes using mean differences with 95% CIs. We quantified statistical heterogeneity using the I 2 statistic. For trials with multiple study groups, we pooled the data for all relevant groups in the same trial before including the study in any meta-analysis so that the same groups were never represented more than once in any given meta-analysis. Where measures of variance were not re- ported in the studies, we imputed the variance from the largest reported SD in the given meta-analysis. We conducted subgroup and sensitivity analyses for illness or disorder subtypes, sex, age group (18 to 35 years,

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36 to 54 years, and 55 to 64 years), race, comorbid condi- tions, drug dosage, follow-up period, previous exposure to antipsychotics, treatment of a first episode versus prior ep- isodes, and treatment resistance. Details of these analyses are presented in the appendices to the full technical report. We report subgroup and sensitivity analyses if there was substantial heterogeneity (I 2 50%). For comparisons with at least 10 studies, we assessed publication bias using funnel plots and statistical tests (27–29). For our primary outcome of core symptoms, we considered a difference of 20% to be clinically important (7, 30). We calculated ab- solute differences (that is, risk differences) for adverse events to enhance interpretation of results.

Role of the Funding Source

The Agency for Healthcare Research and Quality sug- gested the initial questions and approved copyright asser- tion for the manuscript but did not participate in the lit- erature search, data analysis, or interpretation of the results.

RESULTS

A total of 9703 unique study reports were identified; we included 114 primary publications (2, 31–143) (110 RCTs, 2 non-RCTs, and 2 retrospective cohort studies) and 149 companion publications (Figure). The studies were published between 1974 and 2012 and involved 22 drug comparisons. Most studies were multicenter (54%), involved inpatients (48%), and were conducted in North America (42%). The number of participants ranged from 10 to 118 522 (median, 78; interquartile range, 38 to 296). The average participant age ranged from 21 to 50 years (median, 37 years; interquartile range, 32 to 40 years). The length of follow-up (that is, study duration) ranged from less than 1 day to 4 years (median, 8 weeks;

ranged from less than 1 day to 4 years (median, 8 weeks; 501 2 October 2012
ranged from less than 1 day to 4 years (median, 8 weeks; 501 2 October 2012
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Table 2. Summary of Results for Other Outcomes

Review

First- vs. Second-Generation Antipsychotics in Adults With Schizophrenia

Variable and Comparison

Events/Participants, n/N*

Effect Estimate (95% CI)

Medication adherence

FGAs

SGAs

Chlorpromazine vs. clozapine

8/83

21/81

RR, 0.37 (0.17 to 0.79)†

Haloperidol vs. aripiprazole‡

0/33

1/66

RR, 0.66 (0.03 to 15.70)

Haloperidol vs. olanzapine

99/153

127/214

RR, 1.12 (0.86 to 1.46)

Haloperidol vs. risperidone

283/361

307/419

RR, 1.04 (0.89 to 1.21)

Time to all-cause medication discontinuation

Perphenazine vs. olanzapine

48

229

MD, 78.70 ( 119.34 to 38.06)†

Perphenazine vs. risperidone

48

221

MD, 33.40 ( 75.18 to 8.38)

Response rates§

Chlorpromazine vs. clozapine

6/169

48/154

RR, 0.13 (0.06 to 0.28)†

Chlorpromazine vs. olanzapine

0/42

3/42

RR, 0.14 (0.01 to 2.68)

Chlorpromazine vs. quetiapine

52/100

65/101

RR, 0.81 (0.64 to 1.02)

Chlorpromazine vs. ziprasidone

85/154

88/152

RR, 0.95 (0.78 to 1.16)

Haloperidol vs. olanzapine

747/1606

1312/2493

RR, 0.86 (0.78 to 0.96)†

Haloperidol vs. clozapine

23/87

43/91

RR, 0.52 (0.22 to 1.23)

Haloperidol vs. quetiapine

275/611

370/810

RR, 0.99 (0.76 to 1.30)

Haloperidol vs. risperidone

641/1113

1404/2374

RR, 0.94 (0.86 to 1.02)

Haloperidol vs. aripiprazole

374/816

652/1369

RR, 1.01 (0.76 to 1.34)

Haloperidol vs. asenapine

49/115

115/220

RR, 0.82 (0.64 to 1.04)

Haloperidol vs. ziprasidone

250/482

489/801

RR, 0.98 (0.74 to 1.30)

Fluphenazine vs. olanzapine

17/30

23/30

RR, 0.74 (0.51 to 1.07)

Fluphenazine vs. quetiapine

2/13

3/12

RR, 0.62 (0.12 to 3.07)

Fluphenazine vs. risperidone

2/13

3/13

RR, 0.67 (0.13 to 3.35)

Perphenazine vs. aripiprazole

36/146

40/154

RR, 0.95 (0.64 to 1.40)

Remission rates Chlorpromazine vs. clozapine

69/95

70/94

RR, 0.69 (0.23 to 2.06)

Haloperidol vs. olanzapine

89/291

133/291

RR, 0.65 (0.45 to 0.94)†

Haloperidol vs. clozapine

1/34

7/37

RR, 0.16 (0.02 to 1.20)

Haloperidol vs. quetiapine

17/103

24/104

RR, 0.72 (0.41 to 1.25)

Haloperidol vs. risperidone

28/87

36/92

RR, 0.84 (0.56 to 1.24)

Haloperidol vs. ziprasidone

99/407

199/678

RR, 0.89 (0.71 to 1.12)

Relapse rates Chlorpromazine vs. clozapine

11/83

13/81

RR, 0.83 (0.39 to 1.73)

Haloperidol vs. risperidone

244/704

179/701

RR, 1.35 (1.17 to 1.57)†

Haloperidol vs. clozapine

2/37

3/38

RR, 0.68 (0.12 to 3.87)

Rates of hospitalization or rehospitalization

Chlorpromazine vs. clozapine

5/83

7/81

RR, 0.70 (0.23 to 2.11)

Haloperidol vs. olanzapine

14/103

18/105

RR, 0.79 (0.42 to 1.51)

Haloperidol vs. quetiapine

14/103

14/104

RR, 1.01 (0.51 to 2.01)

Haloperidol vs. risperidone

28/209

16/213

RR, 1.94 (0.99 to 3.79)

Haloperidol vs. ziprasidone

16/256

5/230

RR, 2.62 (0.99 to 6.97)

Perphenazine vs. olanzapine

41/261

38/336

RR, 1.39 (0.92 to 2.09)

Perphenazine vs. quetiapine

41/261

68/337

RR, 0.78 (0.55 to 1.11)

Perphenazine vs. risperidone

41/261

51/341

RR, 1.05 (0.72 to 1.53)

Perphenazine vs. ziprasidone

41/261

33/185

RR, 0.88 (0.58 to 1.34)

Mean hospital bed days Haloperidol vs. clozapine

218

205

MD, 7.10 ( 19.02 to 4.82)

Haloperidol vs. olanzapine

150

159

MD, 7.10 ( 20.95 to 6.75)

Health-related quality of life 20% improvement Perphenazine vs. aripiprazole QLS

31/146

55/154

RR, 0.59 (0.41 to 0.87)†

Haloperidol vs. ziprasidone

151

448

MD, 12.12 ( 22.06 to 2.17)†

Haloperidol vs. olanzapine

103

227

MD, 2.62 ( 6.39 to 1.15)

Haloperidol vs. risperidone

30

33

MD, 0.10 ( 0.17 to 0.37)

Perphenazine vs. olanzapine

261

336

MD, 0.00 ( 0.16 to 0.16)

Perphenazine vs. quetiapine

261

337

MD, 0.10 ( 0.07 to 0.27)

Perphenazine vs. risperidone

261

341

MD, 0.07 ( 0.24 to 0.10)

Perphenazine vs. ziprasidone

261

185

MD, 0.07 ( 0.27 to 0.13)

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Table 2—Continued

First- vs. Second-Generation Antipsychotics in Adults With Schizophrenia

Review

Variable and Comparison

Events/Participants, n/N*

Effect Estimate (95% CI)

FGAs

SGAs

MANSA Haloperidol vs. olanzapine

103

105

MD, 0.00 ( 1.38 to 1.38)

Haloperidol vs. quetiapine

103

104

MD, 0.00 ( 1.38 to 1.38)

Haloperidol vs. ziprasidone LQLP

103

82

MD, 0.10 ( 1.48 to 1.28)

Haloperidol vs. risperidone

146

143

MD, 0.10 ( 0.20 to 0.40)

Schizophrenia-specific QLS Haloperidol vs. olanzapine Other

132

144

MD, 3.62 ( 8.94 to 1.70)

Haloperidol vs. olanzapine

10

17

MD, 2.05 ( 25.81 to 21.71)

Patient satisfaction Haloperidol vs. aripiprazole

7/33

42/66

RR, 0.33 (0.17 to 0.66)†

Haloperidol vs. clozapine

9/17

11/17

RR, 0.82 (0.46 to 1.45)

Haloperidol vs. risperidone

11/33

17/34

RR, 0.67 (0.37 to 1.20)

Caregiver satisfaction: haloperidol vs. aripiprazole

6/33

38/66

RR, 0.32 (0.15 to 0.67)†

Patients with paid employment in past month Perphenazine vs. olanzapine

19/261

19/336

RR, 1.29 (0.70 to 2.38)

Perphenazine vs. quetiapine

19/261

14/337

RR, 1.75 (0.90 to 3.43)

Perphenazine vs. risperidone

19/261

18/341

RR, 1.38 (0.74 to 2.57)

Perphenazine vs. ziprasidone

19/261

11/185

RR, 1.22 (0.60 to 2.51)

Sexual dysfunction Fluphenazine vs. quetiapine

7/13

3/12

RR, 2.15 (0.72 to 6.48)

Fluphenazine vs. risperidone

7/13

5/13

RR, 1.40 (0.60 to 3.28)

Haloperidol vs. quetiapine

26/103

26/104

RR, 1.01 (0.63 to 1.62)

Haloperidol vs. olanzapine

27/159

34/160

RR, 0.81 (0.52 to 1.24)

Haloperidol vs. ziprasidone

26/103

30/82

RR, 0.69 (0.45 to 1.07)

Haloperidol vs. risperidone

1/76

5/84

RR, 0.30 (0.05 to 1.78)

Alleviation of sexual dysfunction after treatment Fluphenazine vs. quetiapine

1/13

2/12

RR, 0.46 (0.05 to 4.46)

Fluphenazine vs. risperidone

1/13

6/13

RR, 0.17 (0.02 to 1.20)

Patient insight into illness: haloperidol vs. olanzapine

132

131

MD, 1.10 ( 3.95 to 1.75)

Attitude about drugs: haloperidol vs. risperidone

146

143

MD, 0.80 ( 2.12 to 0.52)

Economic independence: haloperidol vs. risperidone

29/50

31/50

RR, 0.94 (0.68 to 1.29)

Positive urine toxicology test result: haloperidol vs. olanzapine

6/15

2/16

RR, 3.20 (0.76 to 13.46)

FGA first-generation antipsychotic; LQLP Lancashire Quality of Life Profile; MANSA Manchester Short Assessment of Quality of Life; MD mean difference; QLS Quality-of-Life Scale; RR risk ratio; SGA second-generation antipsychotic. * For continuous outcomes, only the number of participants is presented. Statistically significant result that favored the SGA. The outcome in this comparison was low adherence. § The definition of “response rate” varied across studies (for example, a 50% reduction on the Positive and Negative Syndrome Scale and a 40% improvement on the Brief Psychiatric Rating Scale).

interquartile range, 6 to 26 weeks) for RCTs and non- RCTs; the cohort studies were 3 and 22 years in duration. The route of medication administration was primarily oral; intramuscular administration occurred in 10 studies (9%). Sixty-eight percent of studies were supported by the phar- maceutical industry. None of the RCTs and non-RCTs had low risk of bias, 67% had unclear risk of bias, and 33% had high risk of bias. Trials were commonly assessed as having unclear risk of bias because of incomplete reporting of sequence generation, allocation concealment, and blinding methods.

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The most common reasons for trials to be assessed as hav- ing high risk of bias were lack of blinding and inadequate handling or reporting of outcome data. Methodological quality of the cohort studies was good; both collected data retrospectively.

Core Illness Symptoms

The findings for core illness symptoms are presented in Table 1. Comparisons and outcomes for which strength of evidence was insufficient (for example, evidence from single trials) to draw a conclusion are not displayed; these

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First- vs. Second-Generation Antipsychotics in Adults With Schizophrenia

Adverse Event and Comparison

Study

Study

Studies

Events/

Events/

Risk Difference

Risk Ratio

Design

Duration

(Participants),

Participants,

Participants,

(95% CI)

(95% CI)

 

n (n)

n/N

n/N

Death

Chlorpromazine vs. clozapine

Overall

2 (214)

0.04 ( 0.14 to 0.06) 0.01 ( 0.02 to 0.05)

– 0.33 (0.01 to 7.81) 2.93 (0.12 to 70.85)

RCT

208 wk

1 (50)

0/25

1/25

RCT

12 mo

1 (164)

1/83

0/81

Haloperidol vs. aripiprazole

Overall

2 (655)

– 0.00 ( 0.01 to 0.01) 0.01 ( 0.03 to 0.02)

RCT

24 h

1 (360)

0/185

0/175

NE 0.77 (0.04 to 15.91)

RCT

24 h

1 (295)

0/60

2/235

The metabolic syndrome

Haloperidol vs. olanzapine

Overall

2 (139)

0.02 ( 0.17 to 0.13)

– 0.82 (0.24 to 2.82)

RCT

12 wk

1 (72)

4/36

5/37

RCT

6 wk

1 (66)

1/31

9/35

0.22 ( 0.38 to 0.07) 0.13 (0.02 to 0.93)

Tardive dyskinesia Chlorpromazine vs. clozapine

Overall

2 (204)

RCT

9 y

1 (164)

17/83

9/81

– 0.09 ( 0.02 to 0.20) 0.05 ( 0.08 to 0.18)

– 1.84 (0.87 to 3.89) 3.30 (0.14 to 76.46)

RCT

12 wk

1 (40)

1/19

0/21

NE not estimable; RCT randomized, controlled trial.

results for the Positive and Negative Syndrome Scale (PANSS) are displayed in Appendix Table 5 (available at www.annals.org). The following sections describe the re- sults for which there was at least low strength of evidence. Two differences were found in positive symptom alle- viation in comparisons of haloperidol with 5 SGAs, as measured by the PANSS and the Scale for the Assessment of Positive Symptoms. Low-strength evidence showed a benefit for risperidone compared with haloperidol on the PANSS; the difference was not considered clinically im- portant, and there was indication of publication bias. Moderate-strength evidence showed a clinically important benefit of haloperidol over olanzapine on the Scale for the Assessment of Positive Symptoms (Appendix Figure 1, available at www.annals.org). The low strength of evidence for all remaining comparisons was driven by lack of preci- sion in effect estimates. Evidence of benefit for treating negative symptoms with SGAs was stronger. Haloperidol was compared with 6 SGAs by using the PANSS and the Scale for the Assess- ment of Negative Symptoms. Moderate-strength evidence showed that olanzapine had a clinically important benefit compared with haloperidol for both scales (Appendix Fig- ure 2, available at www.annals.org), with no indication of publication bias. Risperidone also showed moderate- strength evidence of benefit compared with haloperidol on the PANSS, although results were not considered clinically important. There was also no indication of publication bias. Aripiprazole showed moderate-strength evidence of benefit compared with haloperidol, although the difference was not considered clinically important. Strength of evi- dence for haloperidol versus clozapine, quetiapine, and ziprasidone was low due to lack of precision in effect estimates.

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There were few differences between FGAs and SGAs in global rating and total symptom score improvement. Moderate-strength evidence showed that olanzapine had a clinically important benefit compared with haloperidol on the PANSS (Appendix Figure 3, available at www.annals .org), with no indication of publication bias. Olanzapine also showed a difference compared with haloperidol on the Clinical Global Impression—Severity scale, but it was not considered clinically important. Moderate-strength evi- dence showed a clinically important benefit of risperidone compared with haloperidol on the PANSS (Appendix Fig- ure 4, available at www.annals.org), although there was substantial heterogeneity (I 2 76%). When 1 outlier (sig- nificantly favoring haloperidol) was removed, heterogene-

ity decreased and results remained in favor of risperidone

( Appendix Figure 5, available at www.annals.org); there

was no indication of publication bias. The outlying study

( n 100) used a relatively small fixed dose of risperidone

(2 mg/d), whereas most of the other studies used a range from 1 mg/d to 5 to 20 mg/d. Subgroup analyses by dosage showed less heterogeneity and more benefits for higher doses of risperidone (data in technical report). Moderate- strength evidence showed a benefit for haloperidol com- pared with quetiapine on the Clinical Global Impression— Severity scale, but the difference was not clinically important. Moderate-strength evidence showed a clinically important benefit for clozapine compared with chlorprom- azine based on the total score from the Brief Psychiatric Rating Scale (Appendix Figure 6, available at www.annals .org). Haloperidol was compared with 4 SGAs, most com- monly olanzapine, and results were reported for 8 scales assessing an overall change in general psychopathology. Moderate-strength evidence showed a difference for 1 of

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Table 3—Continued

Risk of

Consistency

Directness

Precision

Strength of

Bias

Evidence

Medium

Consistent

Direct

Imprecise

Low

– –

––

– –

––

Medium

Consistent

Direct

Imprecise

Low

– –

––

– –

––

Medium

Consistent

Direct

Imprecise

Low

– –

––

– –

––

Medium

Consistent

Direct

Imprecise

Low

– –

– –

––

––

14 comparisons: Olanzapine showed a clinically important benefit on the Montgomery–Asberg Depression Rating Scale (Appendix Figure 7, available at www.annals.org).

Response, Remission, and Relapse Rates and Medication Adherence

Findings for these outcomes are presented in Table 2 and were available for 17 head-to-head comparisons. A statistically significant difference in response rates was found favoring clozapine over chlorpromazine (3 studies) (75, 84, 91). Olanzapine was favored over haloperidol for remission (3 trials) (88, 144, 145) and response rates (14 trials) (40, 85, 88, 98, 101–103, 107, 112, 126, 135, 140, 144, 145). Risperidone was favored over haloperidol for relapse rates (6 trials) (63, 67, 110, 115, 127, 130). Olan- zapine was favored over perphenazine for time to all-cause medication discontinuation (37). Clozapine was favored over chlorpromazine for medication adherence (77). These last 2 findings are based on single studies and should be interpreted with caution.

Patient-Oriented Outcomes and Health Care System Use

Patient-oriented outcomes broadly refer to functional outcomes (for example, sexual dysfunction, employment, and economic independence) and outcomes that are im- portant to patients (for example, health-related quality of life). Results for functional outcomes were available for 9 head-to-head comparisons (Table 2), with no statistically significant differences in any comparisons. In terms of health-related quality of life, aripiprazole compared with perphenazine showed 20% improvement (1 trial) (90), and ziprasidone compared with haloperidol showed benefits on the Quality-of-Life Scale (1 trial) (118). Statistically signif- icant differences were found favoring aripiprazole over hal- operidol for caregiver satisfaction (1 trial) (66) and patient satisfaction (1 trial) (66). Results for health care system use

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were available for 10 head-to-head comparisons, with no statistically significant differences for any comparison (Ta- ble 2). Some of the results described in this section and Table 2 are based on single trials and should be interpreted with caution.

Medication-Associated Adverse Events and Safety

For the 4 key adverse events, the strength of evidence was insufficient to draw conclusions for most comparisons ( Appendix Table 6, available at www.annals.org). Two tri- als each provided data on mortality for chlorpromazine versus clozapine (105, 106) and haloperidol versus arip- iprazole (Table 3) (34, 136). Absolute differences were small, ranging from 1% to 4% and 0% to 1%, respectively. The length of follow-up (that is, duration) of the trials for the latter comparison was only 24 hours, and the drug was administered via intramuscular injection in both studies. Low-strength evidence showed a higher incidence of the metabolic syndrome for olanzapine than for haloperidol; risk differences were 2% and 22%, respectively, in the 2 relevant studies (88, 102). Low-strength evidence showed a higher incidence of tardive dyskinesia for chlorpromazine than for clozapine; risk differences were 5% and 9% at 12 weeks and 9 years, respectively (77, 84). Across all studies involving adverse events, the strength of evidence was driven by lack of precision in the estimates of effect be- cause of the small numbers of participants studied and events observed. Data were also recorded for general measures of ad- verse events and specific adverse events by physiologic sys- tem; extrapyramidal symptoms were the most frequently reported event (detailed data and analyses available in tech- nical report). For general measures of adverse events, sta- tistically significant differences were found in the incidence of adverse events and withdrawals due to adverse events for several comparisons. The comparison usually included hal- operidol, and the risk was consistently higher with the FGA.

DISCUSSION

Despite FGAs and SGAs being a mainstay in the treat- ment of schizophrenia in adults, questions remain about whether and how the various commercially available med- ications differ in efficacy and safety profiles (1– 6). This review provides a comprehensive synthesis of the evidence on the comparative benefits and harms of FDA-approved FGAs and SGAs. We used a broad approach to inclusion criteria for comparisons, patients, and study outcomes to bring together the diversity of previously published reviews and provide a broader perspective on evidence in the field (1, 7–19). We identified a large number of relevant studies (114 studies and 22 different comparisons), the majority of which were efficacy trials (146). The most frequent com- parisons involved haloperidol and risperidone (40 studies) or olanzapine (35 studies); however, the number of studies

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available for each comparison and outcome was often limited. Overall, we found few differences of clinical impor- tance between the active drugs; however, this does not im- ply that they are equivalent. The strength of evidence from these studies was generally low or insufficient, with consid- erable variation in scales and subscales used to measure symptoms. This heterogeneity, coupled with the small number of studies within specific comparisons, suggests that there is insufficient power to explain some of the neg- ative findings and precludes firm conclusions that are needed for front-line clinical decision making. At this time, evidence supporting the use of SGAs for negative symptoms is stronger than that supporting their use for positive symptoms; olanzapine and risperidone were found to be more efficacious than haloperidol in reducing such symptoms as blunted affect and withdrawal. This ef- fect, however, was not observed for improving overall (global) functioning and general psychopathology. Con- trary to recent reviews (7, 8), we found no evidence of benefit in improving symptoms with clozapine compared with haloperidol, although moderate-strength evidence showed benefits for clozapine compared with chlorproma- zine. Differences in study inclusion criteria between our review and previously published reviews probably account for the different outcomes, with our review including more studies from which to base conclusions. In light of the totality of evidence in this review, the ample low-quality evidence showing no difference between haloperidol and various SGAs in improving symptoms provides an inade- quate evidence base to advocate for one medication over another. The data for adverse events were of low to insufficient strength, suggesting the need for a more focused evaluation of drug safety. Despite our efforts to identify long-term safety data from observational studies, only 2 retrospective cohort studies provided follow-up data at least 2 years in duration. Short-term efficacy trials, which are accepted by the regulatory authorities, may not identify time- dependent adverse events, such as tardive dyskinesia, dia- betes mellitus, the metabolic syndrome, or death. Although few studies measured mortality, some evidence suggests that treatment with FGAs or SGAs is no different after immediate use (within 24 hours) or long-term use ( 12 months). The strength of evidence for other mortality- related outcomes (such as suicide-related behaviors, which is a risk in this clinical population) (147–149) was insuffi- cient to draw conclusions. We found low-strength evidence for an increased in- cidence of the metabolic syndrome with use of olanzapine. In general, most studies showed no difference between FGAs and SGAs in terms of increased risk for the meta- bolic syndrome or diabetes mellitus; however, the strength of evidence was usually insufficient. Although the method- ological and reporting limitations of these studies make

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conclusions about these outcomes premature (150), several reviews have identified clozapine and olanzapine as con- tributing to greater weight gain (7, 151–153), but this may not necessarily translate into increased risk for more severe outcomes. Further study of this trajectory is warranted with higher-quality longitudinal studies. Our results are consistent with those of CATIE (Clin- ical Antipsychotic Trials of Intervention Effectiveness) (2), a widely cited trial in this field. CATIE was designed to evaluate whether FGAs were inferior to SGAs in efficacy and safety. Findings from CATIE suggested that the FGA perphenazine and various SGAs (olanzapine, quetiapine, risperidone, and ziprasidone) differed more in their adverse effect profiles than in their therapeutic effect profiles. The study, like this review, also showed that effectiveness across medications varied and that the difference was clinically important in some cases. Our results are also similar to those of a recent system- atic review of SGAs versus FGAs, although our review is broader in scope in terms of medications included, patient populations, and outcomes (1). There were several meth- odological differences between the previous review and this one: The previous review included non–FDA-approved antipsychotics, restricted the analysis to only double-blind trials, included only studies examining optimum SGA dos- age and oral route of administration, pooled data across efficacy outcome measures, and pooled different FGAs. The different methodologies may have led to slightly dif- ferent conclusions about individual SGAs. One of the unique features of our review is the strength-of-evidence assessments, which provide informa- tion on the level of confidence one can place on the results of existing studies. In most cases, the strength of evidence was insufficient or low, highlighting the likelihood that future research may change the estimates of effect and the need for a stronger evidence base to inform clinical prac- tice. Current treatment guidelines from the American Psy- chiatric Association for patients with schizophrenia provide specific recommendations on medication timing (for exam- ple, acute phase or first episode) but broad variables for medication options (154). This approach may reflect the current state of evidence for FGAs and SGAs, and as stron- ger evidence emerges, it may come to reflect more specific recommendations for prescribing physicians. There were limitations in the design and quality of the primary studies. Most studies were short-term RCTs, often with an a priori hypothesis that the SGA would be more efficacious (155). Most trials did not sufficiently report methods to prevent selection and performance bias. Few trials reported blinding study investigators and partici- pants; single-blinded and open-label trials in this field have been found to favor SGAs over FGAs (1). Furthermore, the individual studies and, in many cases, the pooled re- sults may not have sufficient power to detect equivalence or noninferiority between drugs.

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Most studies in this review were industry-funded (69%), which can increase the chance of proindustry find- ings (156). Funding was not disclosed for 19% of studies, highlighting the need for transparency in reporting the na- ture and extent of financial support. The choice of medi- cation comparisons, dosages, and outcomes in the studies included in this review may have been driven by the funder’s interests and priorities. Publication and reporting of select comparisons and outcomes are other potential limitations of this body of evidence. Few studies provided evidence for comparable patient populations. We found notable heterogeneity across stud- ies for disorder subtypes, comorbid drug or alcohol use, treatment resistance, and number of previous episodes, which result in differential response to treatment. Further- more, many studies were highly selective in patient enroll- ment, which may increase the likelihood of drug benefit and decrease the likelihood of adverse events. Detailed sub- group analyses are reported elsewhere (21). Characteristics of the research, including drug dosages (for example, lower doses of FGAs in more recent studies) and patient popu- lations (for example, fewer patients already exposed to FGAs or proven treatment resistance to FGAs in recent studies), also changed over time. Finally, differences in medication comparisons and dosage and outcome mea- surement limited our synthesis, and outcomes that are im- portant for understanding medication adherence and per- sistence (a common clinical encounter in this patient population), such as sedation and restlessness, were rarely reported. More longitudinal research is needed on the long-term safety of FGAs versus SGAs. Despite our efforts to identify long-term safety data from observational studies, only 2 retrospective cohort studies were identified. Consensus is needed on the most important comparisons between FGAs and SGAs for future studies. Short- and long-term evalua- tions with patient subpopulations, including those with medical and neurologic comorbid conditions, are needed. There is a need for studies investigating the influence of dose, age, and other factors, such as comorbid conditions, on serious adverse events, which would help estimate pos- sible risks in specific patient populations. Future studies should also examine functional outcomes that are impor- tant to patients, including health-related quality of life, relationships, academic and occupational performance, and legal interactions. Existing studies on the comparative effectiveness of individual FGAs and SGAs preclude drawing firm conclu- sions because of sparse data and imprecise effect estimates. There were relatively few differences of clinical importance among 114 studies. The current evidence base is inade- quate for clinicians and patients to make informed deci- sions about treatment. Outcomes potentially important to patients were rarely assessed. Data on long-term safety are lacking and urgently needed.

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From University of Alberta, Edmonton, Alberta, Canada, and University of Manitoba/Winnipeg Regional Health Authority, Winnipeg, Mani- toba, Canada.

Acknowledgment: The authors thank Mrs. Carol Spooner and Ms. Ja- nine Schouten for help in article selection and data extraction; Dr. Susan Armijo-Olivo for help in data extraction; Ms. Amy Beaith and Ms. An- drea Milne for help in literature searching; Ms. Annabritt Chisholm and Ms. Teodora Radisic for help in article retrieval; Mr. Ben Vandermeer for help in data analysis; Ms. Jennifer Seida for help in critical review and copyediting; Ms. Christine Ha, Ms. Elizabeth Sumamo Schellenberg, and Mr. Kai Wong for help in screening the gray literature; and the members of the technical expert panel (listed in full technical report).

Grant Support: By the Agency for Healthcare Research and Quality (AHRQ) (contract 290-2007-10021), U.S. Department of Health and Human Services.

Potential Conflicts of Interest: Dr. Hartling: Contract (money to insti- tution): AHRQ. Dr. Abou-Setta: Grant (money to institution): AHRQ. Dr. Dursun: Grants/grants pending (money to institution): CIHR-Canada, Norlien Foundation; Patents (planned, pending, or issued): sodium nitro- prusside for the treatment of schizophrenia, in partnership with the Uni- versity of Alberta, TEC Edmonton Office. Dr. Newton: Grant (money to institution): AHRQ; Other (money paid to author): University of Alberta Evidence-based Practice Center. Disclosures can also be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum M12

-0362.

Requests for Single Reprints: Lisa Hartling, PhD, University of Al- berta, ECHA 4-472, 11405 87 Avenue, Edmonton, Alberta T6G 1C9, Canada; e-mail, hartling@ualberta.ca.

Current author addresses and author contributions are available at www.annals.org.

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